Every year as many as 200,000 patients receive whole brain irradiation (WBI). Most of these patients are treated not for primary brain tumors, but for brain metastases from melanomas, breast cancer or lung cancer that increase in middle age. As patient survival after WBI has increased, 20-50% of the long term survivors develop radiation-induced brain injury, including cognitive impairment. Radiation-induced cognitive impairment occurs in the absence of gross structural pathology, suggesting that this phenomenon is likely preceded by subtle changes in the myelin or the synaptic connections among neurons that underlie cognitive function. However, there have been, i] no quantitative studies of radiation-induced changes in myelin and synapses, ii] no published studies of radiation-induced cognitive impairment with a clinically relevant fractionated course of radiation, and iii] no attempts to ameliorate or prevent this radiation-induced structural or cognitive damage in middle-aged animals. The overall goal of the present grant is to answer the following questions. What changes in myelin and synapses occur when middle-aged rats are given a clinically relevant dose of fractionated WBI? Are the subtle changes in myelin and synapses early predictors of the ensuing radiation-induced cognitive impairment? Will modulation of the intrinsic brain renin-angiotensin system (RAS) ameliorate or prevent this radiation-induced brain injury, including cognitive impairment? Accordingly, the hypotheses to be tested are that, 1) modifications in myelin and synapses are early predictors of radiation-induced brain injury associated with cognitive impairment, and 2) both the structural modifications and the cognitive impairment induced by WBI can be ameliorated or prevented by modulating the intrinsic brain RAS. To test these hypotheses, we will, i] quantify the changes in myelin, synapses and cognition after treating 12 month old F344XBN rats with a clinically relevant course of WBI, and ii] determine if inhibition of the intrinsic brain RAS by administration of ACE inhibitors or Ang II type 1 receptor antagonists will modulate the structural and/or cognitive damage after 12 month old F344XBN rats are treated with fractionated WBI. These studies should provide information that is likely to lead to treatments that ameliorate radiation-induced brain injury, including cognitive impairment;thereby, addressing one of NCI's new areas of public health emphasis.